Doxycycline is a broad spectrum bacteriostatic compound that is effective against Gram-positive, Gram-negative, aerobic and anaerobic bacteria, as well as spirochetes, mycoplasmas, rickettsiae, chlamydiae and some protozoans. It works by inhibiting protein synthesis in bacteria or protozoans. It is commonly used in the treatment of bacterial infections caused by these organisms, such as urinary tract infections, upper respiratory tract infections, acne, gonorrhea, chlamydia, anthrax, lyme disease and others.
Besides antibiotic activity, doxycycline also has some other mechanism of actions like interfering with the chemotaxis of polymorphonuclear leukocytes (PMN) into the inflammatory lesion, inhibition of PMN derived collagenase, scavenging reactive oxidative species produced by resident inflammatory cells etc. Therefore doxycycline is also being used as an anti-inflammatory to treat inflammatory conditions or symptoms, such as diseases like periodontitis, rosacea and acne. In these instances, it is used in an anti-inflammatory effective amount which, may be lower than traditionally prescribed when doxycycline is used for its antibiotic activity.
Doxycycline as an antibiotic is available in 50 mg, 100 mg, and 200 mg oral doses, whereas as for treating periodontitis and rosacea, lower strengths of 20 mg & 40 mg oral doses are marketed as PERIOSTAT® and ORACEA® respectively. These doses can be given once or more per day as directed by a physician. ORACEA® is a 40 mg dose administered once in a 24 hour period. Sustained release formulations of doxycycline are also described in U.S. Pat. Nos. 5,084,287 and 5,188,836.
Oral administration of drugs is frequently affected by food-drug interactions, a phenomenon often described by the term “food effect”. Food effect generally refers to all type of interactions of food with drug which affect its dissolution, absorption, distribution, metabolism and/or elimination. The implications of food effect can, in some instances, include changes in bioavailability, rate of on-set of therapeutic action, duration of therapeutic effect and incidence of side effects.
The food effect is an important issue during the development of a drug. In some cases food-drug interactions lead to an increase of drug absorption and the drug formulation may be recommended to be taken with food in order to be sufficiently absorbed and exert its expected clinical effect. In some other case food interrupts the absorption of active agent and therefore it reduces Cmax and AUC leading to poor therapeutic effect. In those cases, there may be warnings provided to the user to take the drug, for example, one hour before or two hours after eating.
The food effect on doxycycline pharmacokinetics is well known. Indeed, ORACEA® is reported to have 45% and 22% in Cmax and AUC respectively (meaning that the Cmax and AUC of ORACEA® when given in the fed versus fasted state differ by 45% and 22% respectively) and carries the exact dosing restriction noted above.
In addition to its known impact on the gastrointestinal microbiology of a patient, doxycycline is known to have possible adverse gastrological effects which are attributed to irritation of the mucosa. Such effects may include anorexia, nausea, diarrhoea, glossitis, dysphagia, enterocolitis. Further there is huge risk of esophageal irritation and ulceration in patients receiving capsule and tablet forms of the doxycycline, especially when patients immediately go to bed or lie down following dosing, or when the doses are taken without sufficient liquid. Therefore it is necessary the patients should be administered with adequate amounts of fluid or food and the patients are instructed to remain sitting or standing for up to 2 hours post administration to prevent the possible development of oesophageal irritation. Similar restrictions are known for other drug products, like bisphosphonates. These dosing restrictions can understandably cause inconvenience and discomfort to the patients which can impact compliance.
Thus, a need exists to provide a modified release dosage form of doxycycline with reduced or no significant food effect. Further it is desired to have a dosage form of doxycycline which are expected to reduce or prevent risk of esophageal irritation and ulceration in patients and further improves the compliance.